This is a competitive renewal application for a funded project: New CNS dopamine receptor imaging agents (RO1-NS-24538-03). The original purpose of this research project was to develop new iodinated antagonists for SPECT (single photon emission computed tomography) imaging of CNS D-1 and D-2 receptors. In this renewal the project will be expanded to include dopamine receptor agonists and reuptake inhibitors, by which both the pre- and postsynaptic dopamine neuronal systems can be evaluated by the SPECT imaging technique. In the past two years significant progress was made on the development of new D1 and D2 postsynaptic receptor imaging agents. The phase one clinical trial of [123|]|BZM, a D2 dopamine receptor imaging agent, was completed. The safety and feasibility of this agent for human use have been established. Two D1 postsynaptic dopamine receptor imaging agents, FISCH and TISCH, were synthesized and radiolabeled. Animal studies and in vivtro binding studies showed that they are comprising agents. In the next funding period more animal evaluations will be performed, after which one agent will be selected for clinical trials. In order to study the changes in dopamine receptors of various diseases, it is essential to investigate the quantitation of receptors based on the proposed agents and SPECT imaging. In the next funding period we will investigate the quantitation of D2 receptors with [123|]|BZM in conjunction with SPECT imaging. Modeling studies based on planar imaging of monkeys will also be examined, hopefully a relative quantitation technique can be developed. It is likely the radioiodinated ligands developed in this project will be useful in this project in elucidating the physiological and pharmacological properties of the dopaminergic system, and they are also potentially applicable to quantitation, at least relatively, of CNS dopamine receptors in humans.